Endoscopy essentials

Colonoscopy, inflammatory bowel disease

Authors

Helmut Neumann1, 2, Markus F. Neurath1, 2

Institutions

1 2

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1365297 Published online: 19.3.2014 Endoscopy 2014; 46: 322–326 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Helmut Neumann, MD, PhD Department of Medicine I University of ErlangenNuremberg Ulmenweg 18 91054 Erlangen Germany Fax: +49-9131-8535209 [email protected] de

Endoscopy Essentials Reviews in the Endoscopy essentials series cite publications from the past year which, in the authors’ opinion, reflect the state-ofthe-art in endoscopy. Alongside a short summary of each paper, authors explain why they consider their selected articles to be of importance.

Department of Medicine I, University Hospital Erlangen, Erlangen, Germany Ludwig Demling Endoscopic Center of Excellence, University Hospital Erlangen, Germany

A prospective cohort study evaluating a novel colonoscopy platform featuring full-spectrum endoscopy (Gralnek et al., Endoscopy 2013 [1]) !

Despite being the gold standard for the diagnosis and treatment of colorectal neoplasia, standard endoscopy suffers from potential technical limitations that prevent evaluation of the entire large bowel. This is due to the fact that current endoscopes are equipped with charge-coupled device (CCD) or complementary metal oxide semiconductor optics, which allow a field of view of only 170°. As a result, lesions located behind folds may be missed quite easily. Indeed, various studies have shown that a significant proportion of lesions are missed during colonoscopy. Rex et al. reported a 27 % miss rate for adenomas of up to 5 mm in size, 13 % for adenomas 6 – 9 mm in size, and a 6 % miss rate for adenomas of 10 mm or larger, thereby suggesting the need for improvements in colonoscopic technology [2]. In recent years, several attempts have been made to improve adenoma detection rates (ADRs) during colonoscopy. These include the use of transparent distal caps attached to the endoscope, advanced endoscopic imaging techniques, including dyeless chromoendoscopy techniques (i. e. narrow band imaging [NBI], virtual chromoendoscopy), flexible endoscopes with a tip angulation of up to 210°, water aided colonoscopy, and through-the-scope optical devices (e. g. Third Eye Retroscope; Avantis Medical Systems, Inc., Sunnyvale, California, USA) [3, 4]. Although the ADR was improved by most of these technologies, most of them still suffer from inadequate visualization of the area behind the colonic folds. In 2013, full-spectrum endoscopy (FUSE) was introduced as a novel colonoscopy platform. The FUSE flexible colonoscope has a working length of 168 cm and is equipped with a 3.8-mm working channel. Illumination is achieved by seven

Neumann Helmut et al. Colonoscopy, IBD … Endoscopy 2014; 46: 322–326

light-emitting diodes. In particular, the multiple CCD chips in the FUSE colonoscope allow a field " Fig. 1). The first prospecof view of up to 330° (● tive, multicenter study of this device compared standard forward-viewing endoscopy with the FUSE system in an in vitro colon model; significantly more polyps (P < 0.001) were detected by the FUSE system [5]. The prospective, cohort study by Gralnek et al. evaluated, for the first time, the feasibility, usability, and safety of the FUSE platform in patients. A total of 50 patients (aged 18 – 70 years), who were undergoing colonoscopy for colorectal cancer (CRC) screening, polyp surveillance, or diagnostic evaluation, were included. Study end points were cecal intubation rate, time to cecal intubation, withdrawal time, total procedure time, success of therapeutic interventions, adverse events, patient satisfaction, and endoscopists’ subjective evaluation of the FUSE system. The authors reported a cecal intubation rate of 100 %, with a time to reach the cecum of 3.1 ± 1.5 minutes (range 1 – 8 minutes). Withdrawal time was 12.7 ± 4.4 minutes, and total procedure time was 15.3 ± 4.6 minutes (range 5.9 – 28.0 minutes). Therapeutic procedures were performed in 44 % of patients, 27 % of whom underwent polypectomy. The success rate was 100 %, and no adverse events were observed. Patient satisfaction was high, as was endoscopists’ subjective evaluation of the FUSE system, with 94 % of endoscopists reporting the benefit of the FUSE system as “highly significant.” Potential limitations of the study include the nonrandomized approach, no comparison with standard forward-viewing endoscopy, the limited number of patients included without a sample size calculation, and the limited number of endoscopists. Nevertheless, this study by Gralnek et al. presents the first published results of the newly

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Hidden polyp diagnosed with full-spectrum endoscopy (FUSE). FUSE enables a 330 field of view, and images are displayed on three contiguous moni-

introduced FUSE system in humans. The results emerging from this pilot study, together with results from the published in vitro study and recent communications at the Digestive Disease Week and the United European Gastroenterology Week, are encouraging and suggest the potential of the novel FUSE platform to significantly improve CRC screening and surveillance colonoscopy. Studies comparing FUSE with standard forward-viewing endoscopy in a back-to-back and tandem design are already in preparation, and the results of these studies are highly anticipated.

Long-term colorectal-cancer incidence and mortality after lower endoscopy (Nishihara et al., N Engl J Med 2013 [6]) !

Although luminal endoscopy is considered to be the reference standard for CRC and post-polypectomy surveillance, comparable data from randomized, controlled trials are not available. In addition, there is still an ongoing debate on whether the incidence of proximal (i. e. right sided) colon cancer can be reduced by flexible sigmoidoscopy or complete colonoscopy, as a considerable number of patients develop interval cancers after a previous endoscopic examination. For example, no reduction in the incidence of proximal colon cancer was detected in the UK Flexible Sigmoidoscopy Screening Trial, whereas a 14 % reduction was detected in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [7, 8]. Nishihara et al. conducted a prospective analysis of the association between lower gastrointestinal endoscopy and the long term risk of CRC. Data from the Nurses’ Health Study and the Health Professionals Follow-up Study were used, and 88 902 participants were included and followed over a period of 22 years. High risk adenomas were defined as polyps ≥ 10 mm in diameter, tubulovillous or villous histologic features, high grade dysplasia, and three or more adenomatous polyps. In addition, molecular analysis was performed by assessing DNA methylation, microsatellite instability status, and mutation status for BRAF and PIK3CA. The results of this study showed an inverse correlation between CRC incidence and lower gastrointestinal endoscopy. Negative colonoscopy, defined as a procedure that did not result in the diagnosis of colorectal neoplasia, was associated with a lower incidence of CRC within the whole colon, whereas negative sigmoidoscopy was only associated with a lower incidence of distal CRC. This finding was also shown for patients who underwent colonoscopy with polypectomy. The respective multivariate hazard ratios (HRs) for CRC between participants who underwent endoscopy and those who did not were 0.57 after removal of ade-

nomatous polyps, 0.60 after negative sigmoidoscopy, and 0.44 after negative colonoscopy, with consistent findings between men and woman. Polypectomy, negative sigmoidoscopy, and negative colonoscopy were associated with a reduced incidence of distal CRC. A reduced incidence of proximal CRC was only observed in patients with a negative colonoscopy (HR 0.73). Evaluation of the incidence of CRC according to the time since the last colonoscopy, showed hazard ratios of 0.35 for an interval of 3 years or less after a negative colonoscopy, 0.4 for 3 – 5 years, 0.52 for 5 – 10 years, and 0.26 for 10 – 15 years. In addition, a lower incidence of CRC was observed among patients who had previously undergone removal of adenomatous polyps with a surveillance interval of 3 years or less (HR 0.48) and an interval of 3 – 5 years (HR 0.49). For high risk adenomas, a hazard ratio of 0.70 was calculated for colonoscopy performed within 3 – 5 years after the last colonoscopy. Among patients with a family history of CRC, no significant association between colonoscopy and occurrence of CRC was observed beyond 5 years after colonoscopy (HR 0.91). Cancers diagnosed within 5 years after colonoscopy were more likely to be characterized by CIMP, microsatellite instability, and an increased LINE-1 methylation level compared with cancers diagnosed beyond 5 years after colonoscopy or in patients without any prior endoscopy. Taken together, these results show that both screening sigmoidoscopy and screening colonoscopy reduce CRC incidence compared with no endoscopy. Although screening sigmoidoscopy reduces distal CRC, only colonoscopy was associated with lower mortality from proximal colon cancer, thereby suggesting that colonoscopy should be the preferred screening modality. Of note, polypectomy was not associated with a reduced incidence of proximal colon cancer. This may raise the question of whether the presence of an adenoma within the colon may indicate an increased risk for proximal colon cancer. This hypothesis is also strengthened by the fact that more than two-thirds of lesions located in the proximal colon are nonpolypoid lesions (i. e. flat), which can be missed relatively easily [9]. Enhanced imaging technologies may further increase the ADRs within the proximal colon, and prospective multicenter studies addressing this question are therefore highly warranted. In addition, one recent well designed, multicenter study by Knabe et al. showed that systematic biopsies of macroscopically inconspicuous scars after endoscopic resection of large (> 20 mm in diameter), nonpedunculated lesions revealed a significant number of residual adenomas at follow-up [10]. In this context, one recent study by Pohl et al. found that incomplete resection might contribute to the development of interval cancers after colonoscopy

Neumann Helmut et al. Colonoscopy, IBD … Endoscopy 2014; 46: 322–326

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Fig. 1 tors.

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[11]. Finally, it was recently shown that cold forceps polypectomy of diminutive lesions (4 – 5 mm in size), as recommended by common guidelines, yields incomplete histological resection compared with cold snare polypectomy [12]. Taken together, these results indicate that increasing efforts should be made to better understand surveillance strategies after polypectomy, particularly within the right colon.

Diagnostic performance of narrowed spectrum endoscopy, autofluorescence imaging, and confocal laser endomicroscopy for optical diagnosis of colonic polyps: a meta-analysis (Wanders et al., Lancet Oncol 2013 [13]) !

Recently, the American Society for Gastrointestinal Endoscopy (ASGE) proposed the preservation and incorporation of valuable endoscopic innovations (PIVI) statements about real-time in vivo assessment of the histology of diminutive (≤ 5 mm in size) colorectal polyps [14]. The statements included two new attractive paradigms to reduce the costs associated with diminutive colon polyp resection. In order for colorectal polyps ≤ 5 mm in size to be resected and discarded, endoscopic technology should provide at least a 90 % agreement in assignment of post-polypectomy surveillance compared with decisions based on pathological assessment of all identified polyps. Second, in order for a technology to be used to guide the decision to leave suspected hyperplastic polyps ≤ 5 mm in size in place, the technology should provide a negative predictive value (NPV) of more than 90 % for adenomatous polyp histology. The aim of the “resect and discard” strategy is to resect diminutive, nonadenomatous polyps after real-time endoscopic assessment of polyp histology without sending the specimen to the histopathologist, while allowing the endoscopist to make a secure diagnosis. This strategy was calculated to lead to a reduction of 34.5 % in total costs; however, it requires advanced endoscopic imaging modalities to achieve the stipulated NPV. Advanced endoscopic imaging has seen many revolutions over recent years. Developments include the introduction of newer, dyeless chromoendoscopy techniques, autofluorescence imaging (Olympus, Tokyo, Japan), and optical biopsy techniques. Dyeless chromoendoscopy techniques include NBI (Olympus), Fujinon Intelligent Chromoendoscopy (FICE; Fujifilm, Tokyo, Japan), i-scan (Pentax, Tokyo, Japan), compound band imaging (CBI; Aohua, Shanghai, China), and Storz Professional Image Enhancement System (SPIES; Storz, Tuttlingen, Germany). Optical biopsy techniques include confocal laser endomicroscopy (CLE; Pentax; Mauna Kea Technologies, Paris, France), endocytoscopy (Olympus), and WavSTAT (SpectraScience, San Diego, California, USA) [15]. Although most of these imaging technologies have already been widely studied, to date no meta-analysis has been conducted to evaluate the efficacy of most of the available imaging techniques for optical diagnosis of colonic polyps. The meta-analysis by Wanders et al. from the Amsterdam group describes for the first time the sensitivity, specificity, and NPV of NBI, FICE, i-scan, autofluorescence imaging, and CLE for real-time in vivo differentiation of neoplastic and non-neoplastic colonic lesions. The authors performed an extensive literature search according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines by searching databases of Medline, PubMed, EMBASE, and Cochrane Library, and by checking reference lists of respective articles. Overall, 390 separate re-

Neumann Helmut et al. Colonoscopy, IBD … Endoscopy 2014; 46: 322–326

ports were identified, 91 of which were included in the final analysis. A total of 56 studies reported results on NBI, 14 on FICE, 10 on i-scan, and 11 for autofluorescence imaging and CLE, respectively. Over 20 925 lesions were examined in the NBI studies. Pooled sensitivity, specificity, and NPV were 91.5 % (range 88.2 % – 93.9 %), 85.2 % (range 80.0 % – 89.3 %), and 82.5 % (range 75.4 % – 87.9 %), respectively, for real-time in vivo assessment of polyp histology. For FICE, 4492 lesions were evaluated with a sensitivity, specificity, and NPV of 92.5 % (range 87.6 % – 95.6 %), 85.1 % (range 78.7 % – 89.8 %), and 83.7 (range 77.5 % – 88.4 %), respectively. In the i-scan group, 984 lesions were studied, with sensitivity of 89.5 % (82.7 to 93.8), specificity of 89.3 % (81.0 % – 94.2 %), and an NPV of 86.5 % (78.0 % – 92.1 %). A total of 1152 lesions were examined within the studies by using autofluorescence imaging, yielding a sensitivity, specificity, and NPV of 88.0 % (80.5 % – 92.8 %), 69.2 % (51.7 % – 82.4 %), and 81.5 % (54.0 % – 94.3 %), respectively. Finally, CLE was studied in 784 colorectal lesions. The authors reported a sensitivity of 94.3 % (88.1 % – 97.3 %), specificity of 94.8 % (87.3 % – 98.1 %), and NPV of 94.8 % (86.6 % – 98.1 %) for real-time prediction of polyp histology. Potential limitations of the study include the reporting of the overall NPV rather than that for diminutive polyps in the rectosigmoid, as proposed by the PIVI statement. In addition, no distinction between expert and nonexpert endoscopists was made. Recent evidence has shown that experts in endoscopic imaging assess in vivo histology significantly more accurately than nonexperts, but nonexperts can be trained to acquire the skills necessary to adequately perform in vivo diagnosis of diminutive colorectal lesions [16]. Finally, no comparison between the different modalities studied was performed. Despite these limitations, the meta-analysis is of interest for several reasons. Most importantly, only CLE was able to reach the proposed NPV of greater than 90 % for real-time diagnosis of lesions within the colorectum. However, CLE is mostly available only at highly specialized centers, and requires a learning curve and a significantly longer procedure time [17]. In contrast, recent evidence has shown that endoscopists can be trained in image interpretation with NBI in order to adequately predict histology according to the PIVI statement [18], although data showing that this is not possible are also available [19]. Clearly, future research and structured training are highly recommended to address these issues. The meta-analysis has also confirmed the low specificity of currently available autofluorescence imaging for the diagnosis of colonic lesions. Autofluorescence depends on the wavelength of the light source and on tissue characteristics. Based on the differences between the spectra of light that is backscattered between cells, different spectra can be identified that are only relatively specific for various diseases such as ischemia, inflammation, and malignancy. New prototypes are currently under development to solve this problem. Taken together, despite recent developments in the field of advanced endoscopic imaging, standard histology seems to be quite necessary for the diagnosis of colorectal lesions and the recommendation of surveillance intervals.

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Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn’s disease (Bouguen et al., Clin Gastroenterol Hepatol 2013 [20]) !

Traditionally, medical treatment in patients with Crohn’s disease only controls the symptoms, and this approach does not prevent complications, such as the development of strictures, fistulas, abscesses or the requirement for surgery. Over recent years, mucosal healing has become an important end point in patients with inflammatory bowel disease (IBD). Evidence suggests that mucosal healing is predictive of reduced disease activity, decreased need for active treatment, and lower risk of hospitalization and surgery, and thus highlights the importance of endoscopy for monitoring of disease activity. Recently, Neurath and Travis reviewed the end point of mucosal healing in a systematic review, and highlighted the implications of mucosal healing for subsequent clinical management in patients with IBD [21]. The recently introduced European evidence-based consensus for endoscopy in IBD (proposed by the European Crohn’s and Colitis Organisation) defined mucosal healing in Crohn’s disease, in the absence of a formal validation, as the absence of mucosal ulceration, or a Crohn’s disease endoscopic index of severity (CDEIS) score of 0, or a simple endoscopic score for Crohn’s disease (SES-CD) of 0 [22]. Despite the increasing attention of mucosal healing as a treatment goal, to date there have been no studies demonstrating the efficacy and feasibility of using a medical algorithm to reach the goal of mucosal healing (i. e. treat-to-target strategy). In this study by Bouguen et al., the authors evaluated, for the first time, the use of the treat-to-target strategy according to endoscopic disease activity to achieve mucosal healing in clinical practice. Medical records of patients diagnosed and treated between January 2011 and December 2012 were reviewed, and patients with an established diagnosis of Crohn’s disease who had ulcers at baseline endoscopy and who had at least two consecutive endoscopic procedures during the study period were included. Medical records were reviewed for the type and findings of the endoscopic procedure, medical therapies and any adjustments during the study period, and the presence of clinical symptoms at the time of endoscopy and within 3 – 6 months after each endoscopic evaluation. Mucosal healing was defined as the absence of any ulcers and endoscopic improvement was defined as the downgrading of deep ulcers to superficial ulcers or disappearance of superficial ulcers. Of 510 patients, 67 patients were finally included. Mucosal healing was achieved in 19.4 %, 41.8 %, and 50.7 % at 24 weeks, 52 weeks, and 62 weeks of the follow-up period, respectively. In addition, endoscopic improvement with disappearance of ulcers was found in 22.4 %, 49.2 %, and 61.1 % at 24, 52, and 62 weeks, respectively. Patients with mucosal healing had significantly fewer clinical symptoms compared with those with persistent endoscopic activity. However, almost 41 % of patients still suffered from clinical symptoms despite mucosal healing at endoscopy. At univariate analysis, disease duration of less than 2 years and female sex were associated with mucosal healing, whereas previous immunosuppressive drug use and previous abdominal surgery were inversely correlated with mucosal healing. However, these findings were not confirmed in multivariate analysis: factors associated with mucosal healing were fewer than 26 weeks between each endoscopic procedure and adjustment to medical therapy when mucosal healing was not observed.

Although the study suffers from potential limitations, such as the retrospective design at a well-known IBD center, the relatively short follow-up period, and the lack of a randomized control population, the study did show, for the first time, that assessment of endoscopic disease activity and treat-to-target strategies (i. e. adjustment to medical therapy) increase the likelihood of mucosal healing in patients with IBD. The study also demonstrated that performing endoscopic procedures to guide treatment in order to reach the goal of mucosal healing is feasible in clinical practice, and that high rates of mucosal healing are achievable, even among patients with moderate to severe Crohn’s disease. Therefore, the study provided further support to the use of regular endoscopic examinations in patients with IBD. Nevertheless, future prospective and randomized, controlled studies should evaluate this strategy in more detail, including cost effectiveness and potential complications associated with the endoscopic procedure. One recent study showed that, although the risk of adverse events after each endoscopic procedure is similar for patients with IBD and the general population, IBD patients have an increased lifetime risk of complications after colonoscopies [23]. Competing interests: None

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ogy of diminutive colorectal polyps. Gastrointest Endosc 2011; 73: 419 – 422 Tontini GE, Vecchi M, Neurath MF et al. Review article: newer optical and digital chromoendoscopy techniques vs. dye-based chromoendoscopy for diagnosis and surveillance in inflammatory bowel disease. . Aliment Pharmacol Ther 2013; 38: 1198 – 1208 Neumann H, Vieth M, Fry LC. Learning curve of virtual chromoendoscopy for the prediction of hyperplastic and adenomatous colorectal lesions: a prospective 2-center study. Gastrointest Endosc 2013; 78: 115 – 120 Neumann H, Kiesslich R, Wallace MB et al. Confocal laser endomicroscopy: technical advances and clinical applications. Gastroenterology 2010; 139: 388 – 392 Hewett DG, Kaltenbach T, Sano Y et al. Validation of a simple classification system for endoscopic diagnosis of small colorectal polyps using narrow-band imaging. Gastroenterology 2012; 143: 599 – 607

19 Schachschal G, Mayr M, Treszl A et al. Endoscopic versus histological characterisation of polyps during screening colonoscopy. Gut 2014; 63: 458 – 465 [Epub ahead of print] DOI 10.1136/gutjnl-2013-304562 20 Bouguen G, Levesque BG, Pola S et al. Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn’s disease. Clin Gastroenterol Hepatol 2013: [Epub ahead of print] DOI 10.1016/j.cgh.2013.11.005 21 Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 2012; 61: 1619 – 1635 22 Annese V, Daperno M, Rutter MD et al. European evidence based consensus for endoscopy in inflammatory bowel disease. J Crohns Colitis 2013; 7: 982 – 1018 23 Ferreira J, Akbari M, Gashin L et al. Prevalence and lifetime risk of endoscopy-related complications among patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013; 11: 1288 – 1293

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